O-aryl glucoside SGLT2 inhibitors and method

ABSTRACT

wherein  
     when Y is  
                 
 
     or heteroaryl;  
     A is —O(CH 2 ) m , S, —NH(CH 2 ) m , or (CH 2 ) n  where n is 0-3 and m is 0-2;  
     and R 1  to R 6  are as defined herein.  
     A method is also provided for treating diabetes and related diseases employing an SGLT2 inhibiting amount of the above compound alone or in combination with one, two or more other antidiabetic agents, and/or one, two or more hypolipidemic agents.

[0001] This application takes priority from U.S. provisional application No. 60/193,094, filed Mar. 30, 2000.

FIELD OF THE INVENTION

[0002] The present invention relates to O-aryl glucosides which are inhibitors of sodium dependent glucose transporters found in the intestine and kidney (SGLT2) and to a method for treating diabetes, especially type II diabetes, as well as hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis and related diseases, employing such O-aryl glucosides alone or in combination with one, two or more other type antidiabetic agents and/or other type theraeutic agents such as hypolipidemic agents.

BACKGROUND OF THE INVENTION

[0003] Approximately 100 million people worldwide suffer from type II diabetes (NIDDM), which is characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance, the root causes for which are as yet unknown. Hyperglycemia is considered to be the major risk factor for the development of diabetic complications, and is likely to contribute directly to the impairment of insulin secretion seen in advanced NIDDM. Normalization of plasma glucose in NIDDM patients would be predicted to improve insulin action, and to offset the development of diabetic complications. An inhibitor of the sodium-dependent glucose transporter SGLT2 in the kidney would be expected to aid in the normalization of plasma glucose levels, and perhaps body weight, by enhancing glucose excretion.

[0004] The development of novel, safe, and orally active antidiabetic agents is also desired in order to complement existing therapies, including the sulfonylureas, thiazolidinediones, metformin, and insulin, and to avoid the potential side effects associated with the use of these other agents.

[0005] Hyperglycemia is a hallmark of type II diabetes (NIDDM); consistent control of plasma glucose levels in diabetes can offset the development of diabetic complications and beta cell failure seen in advanced disease. Plasma glucose is normally filtered in the kidney in the glomerulus and actively reabsorbed in the proximal tubule. SGLT2 appears to be the major transporter responsible for the reuptake of glucose at this site. The SGLT specific inhibitor phlorizin or closely related analogs inhibit this reuptake process in diabetic rodents and dogs resulting in normalization of plasma glucose levels by promoting glucose excretion without hypoglycemic side effects. Long term (6 month) treatment of Zucker diabetic rats with an SGLT2 inhibitor has been reported to improve insulin response to glycemia, improve insulin sensitivity, and delay the onset of nephropathy and neuropathy in these animals, with no detectable pathology in the kidney and no electrolyte imbalance in plasma. Selective inhibition of SGLT2 in diabetic patients would be expected to normalize plasma glucose by enhancing the excretion of glucose in the urine, thereby improving insulin sensitivity, and delaying the development of diabetic complications.

[0006] Ninety percent of glucose reuptake in the kidney occurs in the epithelial cells of the early S1 segment of the renal cortical proximal tubule, and SGLT2 is likely to be the major transporter responsible for this reuptake. SGLT2 is a 672 amino acid protein containing 14 membrane-spanning segments that is predominantly expressed in the early S1 segment of the renal proximal tubules. The substrate specificity, sodium dependence, and localization of SGLT2 are consistent with the properties of the high capacity, low affinity, sodium-dependent glucose transporter previously characterized in human cortical kidney proximal tubules. In addition, hybrid depletion studies implicate SGLT2 as the predominant Na⁺/glucose cotransporter in the S1 segment of the proximal tubule, since virtually all Na-dependent glucose transport activity encoded in mRNA from rat kidney cortex is inhibited by an antisense oligonucleotide specific to rat SGLT2. SGLT2 is a candidate gene for some forms of familial glucosuria, a genetic abnormality in which renal glucose reabsorption is impaired to varying degrees. None of these syndromes investigated to date map to the SGLT2 locus on chromosome 16. However, the studies of highly homologous rodent SGLTs strongly implicate SGLT2 as the major renal sodium-dependent transporter of glucose and suggest that the glucosuria locus that has been mapped encodes an SGLT2 regulator. Inhibition of SGLT2 would be predicted to reduce plasma glucose levels via enhanced glucose excretion in diabetic patients.

[0007] SGLT1, another Na-dependent glucose cotransporter that is 60% identical to SGLT2 at the amino acid level, is expressed in the small intestine and in the more distal S3 segment of the renal proximal tubule. Despite their sequence similarities, human SGLT1 and SGLT2 are biochemically distinguishable. For SGLT1, the molar ratio of Na⁺ to glucose transported is 2:1, whereas for SGLT2, the ratio is 1:1. The Km for Na⁺ is 32 and 250-300 mM for SGLT1 and SGLT2, respectively. Km values for uptake of glucose and the nonmetabolizable glucose analog α-methyl-D-glucopyranoside (AMG) are similar for SGLT1 and SGLT2, i.e. 0.8 and 1.6 mM (glucose) and 0.4 and 1.6 mM (AMG) for SGLT1 and SGLT2 transporters, respectively. However, the two transporters do vary in their substrate specificities for sugars such as galactose, which is a substrate for SGLT1 only.

[0008] Administration of phlorizin, a specific inhibitor of SGLT activity, provided proof of concept in vivo by promoting glucose excretion, lowering fasting and fed plasma glucose, and promoting glucose utilization without hypoglycemic side effects in several diabetic rodent models and in one canine diabetes model. No adverse effects on plasma ion balance, renal function or renal morphology have been observed as a consequence of phlorizin treatment for as long as two weeks. In addition, no hypoglycemic or other adverse effects have been observed when phlorizin is administered to normal animals, despite the presence of glycosuria. Administration of an inhibitor of renal SGLTs for a 6-month period (Tanabe Seiyaku) was reported to improve fasting and fed plasma glucose, improve insulin secretion and utilization in obese NIDDM rat models, and offset the development of nephropathy and neuropathy in the absence of hypoglycemic or renal side effects.

[0009] Phlorizin itself is unattractive as an oral drug since it is a nonspecific SGLT1/SGLT2 inhibitor that is hydrolyzed in the gut to its aglycone phloretin, which is a potent inhibitor of facilitated glucose transport. Concurrent inhibition of facilitative glucose transporters (GLUTs) is undesirable since such inhibitors would be predicted to exacerbate peripheral insulin resistance as well as promote hypoglycemia in the CNS. Inhibition of SGLT1 could also have serious adverse consequences as is illustrated by the hereditary syndrome glucose/galactose malabsorption (GGM), in which mutations in the SGLT1 cotransporter result in impaired glucose uptake in the intestine, and life-threatening diarrhea and dehydration. The biochemical differences between SGLT2 and SGLT1, as well as the degree of sequence divergence between them, allow for identification of selective SGLT2 inhibitors.

[0010] The familial glycosuria syndromes are conditions in which intestinal glucose transport, and renal transport of other ions and amino acids, are normal. Familial glycosuria patients appear to develop normally, have normal plasma glucose levels, and appear to suffer no major health deficits as a consequence of their disorder, despite sometimes quite high (110-114 g/daily) levels of glucose excreted. The major symptoms evident in these patients include polyphagia, polyuria and polydipsia, and the kidneys appear to be normal in structure and function. Thus, from the evidence available thus far, defects in renal reuptake of glucose appear to have minimal long term negative consequences in otherwise normal individuals.

[0011] The following references disclose O-aryl glucosides SGLT2 inhibitors for treating diabetes.

[0012] EP 598359A1 (also JP 035988) (Tanabe Seiyaku)discloses compounds of the following structure A

[0013] EP 0850948A1 discloses structures of the following genus B

[0014] JP 09188625A expands upon structure B to include examples of B where R³ is H and where the 5 membered ring is saturated as well as the counterparts of benzothiophenes (O═S) and indenes (O═CH₂)

[0015] JP 09124685A expands upon structure B for R³=H to include derivatives of mono acylated C6 hydroxyl where the acyl group is a substituted benzoic or pyridyl carboxylic acid or a urethane generated from the corresponding phenol.

[0016] JP 09124684 discloses derivatives of structure B

[0017] EP 773226-A1 discloses derivatives of structure B

[0018] JP 08027006-A discloses derivatives of structure A where various combinations of the glucose hydroxyl are acylated and appears to be similar to EP 598359A1.

[0019] EP 684254-A1 appears to encompass derivatives of structure B disclosed in JP 09188625A.

[0020] Other disclosures and publications which disclose SGLT2 inhibitors are as following:

[0021] K. Tsujihara, et. al., Chem. Pharm. Bull. 44, 1174-1180 (1996)

[0022] M. Hongu et. al., Chem. Pharm. Bull. 46, 22-33 (1998)

[0023] M. Hongu et. al., Chem. Pharm. Bull. 46, 1545-1555 (1998)

[0024] A. Oku et. al., Diabetes, 48, 1794-1800 (1999).

[0025] JP 10245391 (Dainippon) discloses 500 structures as hypoglycemic agents for treatment of diabetes. These are O-glucosides of hydroxylated coumarins.

[0026] Other references disclosing structures of O-arylglucosides, shown below, which are closely related to the genus disclosed herein are:

[0027] 1) G. K. Jain et. al., Indian J. Chem., 26B, 163-166 (1989)

[0028] 2) A. Levai et. al., Acta Chim. Acad. Sci. Hung., 84, 99-107 (1975)

[0029] 3) H. Kaemmerer et al., Makromol. Chem., 182, 1351-1361 (1981)

DESCRIPTION OF THE INVENTION

[0030] In accordance with the present invention, O-aryl glucoside compounds are provided which have the structure I.

[0031] wherein

[0032] when Y is

[0033] or heteroaryl;

[0034] R¹, R², R³, and R⁴ are the same or different and are independently selected from hydrogen, OH, OR⁷, lower alkyl, or halogen, or two of R¹, R², R³, and R⁴ together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂;

[0035] R⁵ and R⁶ are the same or different and are independently selected from hydrogen, OH, OR^(7a), —OAryl, —OCH₂Aryl, lower alkyl, cycloalkyl, Aryl, arylalkyl, CF₃, arylalkenyl, —OCHF₂, —OCF₃, halogen, —CN, —CO₂R^(7b), —CO₂H, COR^(8f), CHOHR^(8g), CH(OR^(7h))R^(8h), —CONR⁸R^(8a), —NHCOR^(7c), —NHSO₂R^(7d), —NHSO₂Aryl, —SR^(7e), —SOR^(7f), —SO₂R^(7g), —SO₂Aryl, —OCH₂CO₂R^(7i), —OCH₂CO₂H, —OCH₂CONR^(8b)R^(8c), —OCH₂CH₂NR^(8d)R^(8e), or a five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂, or R⁵ and R⁶ together with the carbons to which they are attached form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂;

[0036] R⁷, R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), R^(7f), R^(7g), R^(7h), and R^(7i) are independently lower alkyl;

[0037] R⁸, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g), and R^(8h) are the same or different and are independently selected from hydrogen, alkyl,aryl, arylalkyl, cycloalkyl, or together with the nitrogen to which they are attached form an annelated five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂;

[0038] A is O(CH₂)_(m), S, NH(CH₂)_(m), or (CH₂)_(n) where n is 0-3 and m is 0-2, and a pharmaceutically acceptable salt thereof, all stereoisomers thereof, and all prodrug esters thereof.

[0039] The compounds of formula I of the invention as defined above also include the following provisos that

[0040] where A is CH₂ and Y is

[0041] and when

[0042] 1) R¹ is OH and R³ is alkyl, at least one of R¹, R⁴, R⁵ and R⁶ is not hydrogen, and preferably 4-R⁶ is other than hydrogen;

[0043] 2) R² and R³ are OH, at least one of R¹, R⁴, R⁵ and R⁶ is not hydrogen, and preferably 4-R⁶ is other than hydrogen;

[0044] 3) R² is methyl, R⁵ is OH, and R⁶ is alkyl, at least one of R¹, R³, and R⁴ is not hydrogen; and

[0045] 4) R² is chlorine, at least one of R¹, R³, R⁴, R⁵ and R⁶ is not hydrogen, and preferably 4-R⁶ is other than hydrogen.

[0046] In the compounds of formula I, where A is O(CH₂)_(m) or NH(CH₂)_(m), the heteroatom O or N will be linked to the aryl ring directly joined to the glucoside moiety.

[0047] The compounds of formula I of the invention possess activity as inhibitors of the sodium dependent glucose transporters found in the intestine and kidney of mammals and are useful in the treatment of diabetes and the micro- and macro-vascular complications of diabetes such as retinopathy, neuropathy, nephropathy, and wound healing.

[0048] The present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds and for methods of using such compounds.

[0049] In addition, in accordance with the present invention, a method is provided for treating diabetes, especially type II diabetes and related diseases including complications of diabetes, including retinopathy, neuropathy, nephropathy and wound healing, and related diseases such as insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, elevated blood levels of fatty acids or glycerol, obesity, hypertriglyceridemia, atherosclerosis and hypertension, and for increasing high density lipoprotein levels, wherein a therapeutically effective amount of a compound of structure I of the invention is administered to a human patient in need of treatment.

[0050] In addition, in accordance with the present invention, a method is provided for treating diabetes and related diseases as defined above and hereinafter, wherein a therapeutically effective amount of a combination of a compound of structure I of the invention and one, two or more of other types antidiabetic agents and/or one, two or more other types of therapeutic agents is administered to a human patient in need of treatment.

[0051] The conditions, diseases, and maladies collectively referred to as “Syndrome X” (also known as Metabolic Syndrome) are detailed in Johannsson J. Clin. Endocrinol. Metab., 82, 727-34 (1997).

[0052] The term “other type of therapeutic agents” as employed herein refers to one or more antidiabetic agents (other than SGLT2 inhibitors of formula I), one or more anti-obesity agents, and/or one or more lipid-lowering agents (including anti-atherosclerosis agents).

[0053] In the above method of the invention, the compound of structure I will be employed in a weight ratio to the antidiabetic agent(s) and/or hypolipidemic agent(s) (depending upon its mode of operation) within the range from about 0.01:1 to about 300:1, preferably from about 0.1:1 to about 100:1, and more preferably from about 0.1:1 to about 10:1.

[0054] Preferred are compounds of formula IA

[0055] wherein A is CH₂ or O or S.

[0056] More preferred are compounds of formula IA where A is CH₂;

[0057] R¹ is H, halogen or alkyl;

[0058] R² and R³ are each H;

[0059] R⁵ is H.

[0060] Most preferred are compounds of formula I of the structure IB

[0061] where

[0062] R¹ is hydrogen, halogen or alkyl or R¹ and R⁴ are independently H or alkyl;

[0063] R⁶ is hydrogen, alkyl, R^(7a)O, CHF₂O, CF₃O or R^(7e)S.

[0064] Examples of preferred compounds of formula I of the invention include compounds having the structure

A R¹ R² R³ R⁴ R⁵ CH₂ H H H H 4-MeO CH₂ H H H H 4-tBu CH₂ H H H H 4-MeS CH₂ H H H H 4-iPr CH₂ H H H H 4-Cl CH₂ H H H H 4-CF₃ CH₂ H H H H 4-CF₃O CH₂ Me H H H H CH₂ H H H Me 4-MeS CH₂ H H H Me 4-Me CH₂ Cl H H H H

DETAILED DESCRIPTION OF THE INVENTION

[0065] The present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds and for methods of using such compounds.

[0066] The compounds of formula I of the invention may be prepared as shown in the following reaction schemes and description thereof wherein temperatures are expressed in degrees Centigrade.

[0067] Compounds of formula I of the invention can be prepared from compounds of formula II

[0068] by treatment of II with a base such as LiOH or NaOH in a solvent such as 3:1 MeOH/H₂O or 3:2:1 MeOH/THF/H₂O.

[0069] Compounds of formula II can be prepared by reacting commercially available 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide III

[0070] with compounds of formula IV

[0071] in the presence of Ag₂O in a solvent such as lutidine or quinoline or in the presence of silver triflate in a solvent such as CH₂Cl₂ containing a base such as 2,6-di-t-butyl-4-methylpyridine.

[0072] Compounds of formula IV where A is (CH₂)_(n) with n=1-3 can be prepared from compounds of formula V

[0073] by treatment with H₂ in a solvent such as MeOH or EtOH in the presence of a catalyst such as Pd/C.

[0074] Compounds of formula V are either commercially available or readily prepared by acylation of compounds of formula VI.

[0075] with compounds of formula VII

[0076] by a variety of methods familiar to those skilled in the arts.

[0077] Compounds of formula IV where A is (CH₂)₂ can be prepared from commercially available compounds of formula VIII

[0078] by treatment of VIII with H₂ in a solvent such as MeOH or EtOH in the presence of a catalyst such as Pd/C.

[0079] Compounds of formula IV where A is CH₂ can be prepared by alkylation of compounds formula VI with commercially available compounds of formula IX

[0080] using a solvent such as toluene and a base such as NaH provided that the aryl or heteroaryl ring of IX is not electron deficient i.e. the total Hammet σ for the substituents R⁵ and R⁶ is less than ˜+0.3.

[0081] Compounds of formula IV where A is CH₂ can also be prepared from compounds of formula X

[0082] by reduction of X by with H₂ in a solvent such as MeOH or EtOH in the presence of a catalyst such as Pd/C or with a silane such as Et₃SiH in a solvent such as MeCN containing a Lewis acid such as TFA or BF₃.Et₂O.

[0083] Compounds of formula X are readily obtained by the reaction of commercially available compounds of formula XI

[0084] with the Mg⁺² or Li⁺ organometalic prepared from aryl or heteroaryl bromides or chlorides of formula XII XII

Br—Y

[0085] using the procedures available to those skilled in the art.

[0086] As seen in Scheme 2, compounds of formula IV where A is O can also be prepared by treating compounds of formula XIII

[0087] with H₂ in a solvent such as MeOH or EtOH using a catalyst such as Pd/C. Compounds of formula XIII can be prepared by reacting compounds of formula XIV

[0088] in a solvent such as pyridine containing Et₃N, molecular sieves, and Cu(OAc)₂ with compounds of formula XV

[0089] Compounds of formula XIV are either commercially available or can prepared from the corresponding catechol XVI

[0090] upon alkylation of XVI with one equivalent of benzyl bromide or chloride using procedures well known to those skilled in the art.

[0091] Compounds of formula XV are commercially available or can be obtained upon treatment of XVII with BCl₃ at −75° in a solvent such as CH₂Cl₂.

[0092] Compounds of formula XVII can be prepared upon heating compounds of formula XII

[0093] in a solvent such as DMSO containing a catalyst such as PdCl₂.dppf and a base such as KOAc with compound XVIII.

[0094] with H₂ in a solvent such as MeOH or EtOH using a catalyst such as Pd/C. Compounds of formula XIX are commercially available or may be prepared by alkylation of the compounds of formula XVI in a solvent such as acetone containing a base such as K₂CO₃ with commercially available phenacyl chloride or bromide of formula XX.

[0095] Compounds of formula IV where A is S can be prepared by treating compounds of formula XXI

[0096] with 2 equivalents of t-BuLi at −78° in a solvent such as THF prior to the addition of compounds of formula XXII

[0097] As seen in Scheme 3, compounds of formula II where A is NH can be prepared by treating compounds of formula XXIII

[0098] with compounds of formula XV in a solvent such as Et₃N containing Cu(OAc) 2 and molecular sieves.

[0099] Compounds of formula XXIII can be prepared by treatment of compounds of formula XXIV

[0100] with H₂ using a catalyst such as Pd/C in a solvent such as MeOH or EtOH.

[0101] Compounds of formula XXIV can be prepared by coupling compounds of formula III with compounds of formula XXV

[0102] in a solvent such as lutidine or quinoline containing Ag₂O.

[0103] Compounds of formula II where A is NHCH₂ can be prepared by coupling compounds of formula XXIII with compounds of formula XXVI

[0104] by stirring in a solvent such as HOAc with a reducing agent such as NaCNBH₃.

[0105] Compounds of formula II where A is NHCH₂CH₂ can be prepared by coupling compounds of formula XXIII with compounds of formula XXVII

[0106] by stirring in a solvent such as HOAc with a reducing agent such as NaCNBH₃.

[0107] Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.

[0108] The following abbreviations are employed herein:

[0109] Ph=phenyl

[0110] Bn=benzyl

[0111] t-Bu=tertiary butyl

[0112] Me=methyl

[0113] Et=ethyl

[0114] TMS=trimethylsilyl

[0115] TMSN₃=trimethylsilyl azide

[0116] TBS=tert-butyldimethylsilyl

[0117] THF=tetrahydrofuran

[0118] Et₂O=diethyl ether

[0119] EtOAc=ethyl acetate

[0120] DMF=dimethyl formamide

[0121] MeOH=methanol

[0122] EtOH=ethanol

[0123] i-PrOH=isopropanol

[0124] HOAc or AcOH=acetic acid

[0125] TFA=trifluoroacetic acid

[0126] i-Pr₂NEt=diisopropylethylamine

[0127] Et₃N=triethylamine

[0128] DMAP=4-dimethylaminopyridine

[0129] NaBH₄=sodium borohydride

[0130] LiAlH₄=lithium aluminum hydride

[0131] n-BuLi=n-butyllithium

[0132] Pd/C=palladium on carbon

[0133] KOH=potassium hydroxide

[0134] NaOH=sodium hydroxide

[0135] LiOH=lithium hydroxide

[0136] K₂CO₃=potassium carbonate

[0137] NaHCO₃=sodium bicarbonate

[0138] EDC (or EDC.HCl) or EDCI (or EDCI.HCl) or EDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)

[0139] HOBT or HOBT.H₂O=1-hydroxybenzotriazole hydrate

[0140] HOAT=1-Hydroxy-7-azabenzotriazole

[0141] Ph₃P=triphenylphosphine

[0142] Pd(OAc)₂=Palladium acetate

[0143] (Ph₃P)₄Pd°=tetrakis triphenylphosphine palladium

[0144] Ar=argon

[0145] N₂=nitrogen

[0146] min=minute(s)

[0147] h or hr=hour(s)

[0148] L=liter

[0149] mL=milliliter

[0150] L=microliter

[0151] g=gram(s)

[0152] mg=milligram(s)

[0153] mol=moles

[0154] mmol=millimole(s)

[0155] meq=milliequivalent

[0156] RT=room temperature

[0157] sat or sat'd=saturated

[0158] aq.=aqueous

[0159] TLC=thin layer chromatography

[0160] HPLC=high performance liquid chromatography

[0161] LC/MS=high performance liquid chromatography/mass spectrometry

[0162] MS or Mass Spec=mass spectrometry

[0163] NMR=nuclear magnetic resonance

[0164] mp=melting point

[0165] dppf=diphenylphosphinoferrocene

[0166] DCE=1,2-dichloroethane

[0167] Unless otherwise indicated, the term “lower alkyl”, “alkyl” or “alk” as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 20 carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including 1 to 4 substituents such as halo, for example F, Br, Cl or I or CF₃, alkyl, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkyloxy, optionally substituted amino, hydroxy, hydroxyalkyl, acyl, oxo, alkanoyl, heteroaryl, heteroaryloxy, cycloheteroalkyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and/or alkylthio.

[0168] Unless otherwise indicated, the term “cycloalkyl” as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 10 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,

[0169] any of which groups may be optionally substituted with 1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio and/or any of the alkyl substituents.

[0170] The term “cycloalkenyl” as employed herein alone or as part of another group refers to cyclic hydrocarbons containing 3 to 12 carbons, preferably 5 to 10 carbons and 1 or 2 double bonds. Exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, and cycloheptadienyl, which may be optionally substituted as defined for cycloalkyl.

[0171] The term “alkanoyl” as used herein alone or as part of another group refers to alkyl linked to a carbonyl group.

[0172] Unless otherwise indicated, the term “lower alkenyl” or “alkenyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 1 to 8 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, alkylthio and/or any of the alkyl substituents set out herein.

[0173] Unless otherwise indicated, the term “lower alkynyl” or “alkynyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, and/or any of the alkyl substituents set out herein.

[0174] The terms “arylakyl”, “arylalkenyl” and “arylalkynyl” as used alone or as part of another group refer to alkyl, alkenyl and alkynyl groups as described above having an aryl substituent.

[0175] Where alkyl groups as defined above have single bonds for attachment to other groups at two different carbon atoms, they are termed “alkylene” groups and may optionally be substituted as defined above for “alkyl”.

[0176] Where alkenyl groups as defined above and alkynyl groups as defined above, respectively, have single bonds for attachment at two different carbon atoms, they are termed “alkenylene groups” and “alkynylene groups”, respectively, and may optionally be substituted as defined above for “alkenyl” and “alkynyl”.

[0177] Suitable alkylene, alkenylene or alkynylene groups (CH₂)_(m), (CH₂)_(n) or (CH₂)_(p) (where p can be 1 to 8, preferably 1 to 5, which includes alkylene, alkenylene or alkynylene groups as defined herein), may optionally include 1, 2, or 3 substituents which include alkyl, alkenyl, halogen, cyano, hydroxy, alkoxy, amino, thioalkyl, keto, C₃-C₆ cycloalkyl, alkylcarbonylamino or alkylcarbonyloxy.

[0178] Examples of (CH₂)_(m), (CH₂)_(n) or (CH₂)_(p), alkylene, alkenylene and alkynylene include —CH₂—, —CH₂CH₂—,

[0179] The term “halogen” or “halo” as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine, with chlorine or fluorine being preferred.

[0180] The term “metal ion” refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum.

[0181] Unless otherwise indicated, the term “aryl” or “Aryl” as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl) and may optionally include one to three additional rings fused to a carbocyclic ring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings for example

[0182] and may be optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl and/or any of the alkyl substituents set out herein.

[0183] Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”, “aryloxy” or “aralkoxy” as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom.

[0184] Unless otherwise indicated, the term “substituted amino” as employed herein alone or as part of another group refers to amino substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituents may be further substituted with a carboxylic acid and/or any of the alkyl substituents as set out above. In addition, the amino substituents may be taken together with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-l-piperazinyl, 4-arylalkyl-l-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy.

[0185] Unless otherwise indicated, the term “lower alkylthio”, “alkylthio”, “arylthio” or “aralkylthio” as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom.

[0186] Unless otherwise indicated, the term “lower alkylamino”, “alkylamino”, “arylamino”, or “arylalkylamino” as employed herein alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.

[0187] Unless otherwise indicated, the term “acyl” as employed herein by itself or part of another group, as defined herein, refers to an organic radical linked to a carbonyl

[0188] group; examples of acyl groups include any of the alkyl substituents attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl and the like.

[0189] Unless otherwise indicated, the term “cycloheteroalkyl” as used herein alone or as part of another group refers to a 5-, 6- or 7-membered saturated or partially unsaturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH₂)_(p) (where p is 1, 2 or 3), such as

[0190] and the like. The above groups may include 1 to 4 substituents such as alkyl, halo, oxo and/or any of of the alkyl substituents set out herein. In addition, any of the cycloheteroalkyl rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

[0191] Unless otherwise indicated, the term “heteroaryl” as used herein alone or as part of another group refers to a 5- or 6-membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), and includes possible N-oxides. The heteroaryl group may optionally include 1 to 4 substituents such as any of the the alkyl substituents set out above. Examples of heteroaryl groups include the following:

[0192] and the like.

[0193] The term “cycloheteroalkylalkyl” as used herein alone or as part of another group refers to cycloheteroalkyl groups as defined above linked through a C atom or heteroatom to a (CH₂)_(p) chain.

[0194] The term “heteroarylalkyl” or “heteroarylalkenyl” as used herein alone or as part of another group refers to a heteroaryl group as defined above linked through a C atom or heteroatom to a —(CH₂)_(p)— chain, alkylene or alkenylene as defined above.

[0195] The term “five, six or seven membered carbocycle or heterocycle” as employed herein refers to cycloalkyl or cycloalkenyl groups as defined above or heteroaryl groups or cycloheteroaryl groups as defined above, such as thiadiazaole, tetrazole, imidazole, or oxazole.

[0196] The term “polyhaloalkyl” as used herein refers to an “alkyl” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF₃CH₂, CF₃ or CF₃CF₂CH₂.

[0197] The term “polyhaloalkyloxy” as used herein refers to an “alkoxy” or “alkyloxy” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF₃CH₂O, CF₃O or CF₃CF₂CH₂O.

[0198] The term “prodrug esters” as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of formula I with alkyl, alkoxy, or aryl substituted acylating agents employing procedures known to those skilled in the art to generate acetates, pivalates, methylcarbonates, benzoates and the like. In addition, prodrug esters which are known in the art for carboxylic and phosphorus acid esters such as methyl, ethyl, benzyl and the like.

[0199] Examples of such prodrug esters include

[0200] Other examples of suitable prodrug esters include

[0201] wherein R^(a) can be H, alkyl (such as methyl or t-butyl), arylalkyl (such as benzyl) or aryl (such as phenyl); R^(d) is H, alkyl, halogen or alkoxy, R^(e) is alkyl, aryl, arylalkyl or alkoxyl, and n₁ is 0, 1 or 2.

[0202] Where the compounds of structure I are in acid form they may form a pharmaceutically acceptable salt such as alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium as well as zinc or aluminum and other cations such as ammonium, choline, diethanolamine, lysine (D or L), ethylenediamine, t-butylamine, t-octylamine, tris-(hydroxymethyl)aminomethane (TRIS), N-methyl glucosamine (NMG), triethanolamine and dehydroabietylamine.

[0203] All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substituents. Consequently, compounds of formula I can exist in enantiomeric or diastereomeric forms or in mixtures thereof. The processes for preparation can utilize racemates, enantiomers or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization.

[0204] Where desired, the compounds of structure I may be used in combination with one or more other types of antidiabetic agents and/or one or more other types of therapeutic agents which may be administered orally in the same dosage form, in a separate oral dosage form or by injection.

[0205] The other type of antidiabetic agent which may be optionally employed in combination with the SGLT2 inhibitor of formula I may be 1,2,3 or more antidiabetic agents or antihyperglycemic agents including insulin secretagogues or insulin sensitizers, or other antidiabetic agents preferably having a mechanism of action different from SGLT2 inhibition and may include biguanides, sulfonyl ureas, glucosidase inhibitors, PPAR γ agonists, such as thiazolidinediones, aP2 inhibitors, PPAR α/γ dual agonists, dipeptidyl peptidase IV (DP4) inhibitors, and/or meglitinides, as well as insulin, and/or glucagon-like peptide-l (GLP-l).

[0206] It is believed that the use of the compounds of structure I in combination with 1, 2, 3 or more other antidiabetic agents produces antihyperglycemic results greater than that possible from each of these medicaments alone and greater than the combined additive antihyperglycemic effects produced by these medicaments.

[0207] The other antidiabetic agent may be an oral antihyperglycemic agent preferably a biguanide such as metformin or phenformin or salts thereof, preferably metformin HCl.

[0208] Where the other antidiabetic agent is a biguanide, the compounds of structure I will be employed in a weight ratio to biguanide within the range from about 0.01:1 to about 100:1, preferably from about 0.1:1 to about 5:1.

[0209] The other antidiabetic agent may also preferably be a sulfonyl urea such as glyburide (also known as glibenclamide), glimepiride (disclosed in U.S. Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, other known sulfonylureas or other antihyperglycemic agents which act on the ATP-dependent channel of the β-cells, with glyburide and glipizide being preferred, which may be administered in the same or in separate oral dosage forms.

[0210] The compounds of structure I will be employed in a weight ratio to the sulfonyl urea in the range from about 0.01:1 to about 100:1, preferably from about 0.2:1 to about 10:1.

[0211] The oral antidiabetic agent may also be a glucosidase inhibitor such as acarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol (disclosed in U.S. Pat. No. 4,639,436), which may be administered in the same or in a separate oral dosage forms.

[0212] The compounds of structure I will be employed in a weight ratio to the glucosidase inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 50:1.

[0213] The compounds of structure I may be employed in combination with a PPAR γ agonist such as a thiazolidinedione oral anti-diabetic agent or other insulin sensitizers (which has an insulin sensitivity effect in NIDDM patients) such as troglitazone (Warner-Lambert's Rezulin®, disclosed in U.S. Pat. No. 4,572,912), rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016), Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone and pioglitazone.

[0214] The compounds of structure I will be employed in a weight ratio to the thiazolidinedione in an amount within the range from about 0.01:1 to about 100:1, preferably from about 0.2:1 to about 10:1.

[0215] The sulfonyl urea and thiazolidinedione in amounts of less than about 150 mg oral antidiabetic agent may be incorporated in a single tablet with the compounds of structure I.

[0216] The compounds of structure I may also be employed in combination with a antihyperglycemic agent such as insulin or with glucagon-like peptide-l (GLP-l) such as GLP-l (1-36) amide, GLP-l (7-36) amide, GLP-l (7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener, the disclosure of which is incorporated herein by reference), as well as AC2993 (Amylen) and LY-315902 (Lilly), which may be administered via injection, intranasal, or by transdermal or buccal devices.

[0217] Where present, metformin, the sulfonyl ureas, such as glyburide, glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and the glucosidase inhibitors acarbose or miglitol or insulin (injectable, pulmonary, buccal, or oral) may be employed in formulations as described above and in amounts and dosing as indicated in the Physician's Desk Reference (PDR).

[0218] Where present, metformin or salt thereof may be employed in amounts within the range from about 500 to about 2000 mg per day which may be administered in single or divided doses one to four times daily.

[0219] Where present, the thiazolidinedione anti-diabetic agent may be employed in amounts within the range from about 0.01 to about 2000 mg/day which may be administered in single or divided doses one to four times per day.

[0220] Where present insulin may be employed in formulations, amounts and dosing as indicated by the Physician's Desk Reference.

[0221] Where present GLP-1 peptides may be administered in oral buccal formulations, by nasal administration or parenterally as described in U.S. Pat. Nos. 5,346,701 (TheraTech), 5,614,492 and 5,631,224 which are incorporated herein by reference.

[0222] The other antidiabetic agent may also be a PPAR α/γ dual agonist such as AR-HO39242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck) as well as those disclosed by Murakami et al, “A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation—Activated Receptor Alpha (PPAR alpha) and PPAR gamma. Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats”, Diabetes 47, 1841-1847 (1998), and in U.S. provisional application No. 60/155,400, filed Sep. 22, 1999, (attorney file LA29) the disclosure of which is incorporated herein by reference, employing dosages as set out therein, which compounds designated as preferred are preferred for use herein.

[0223] The other antidiabetic agent may be an aP2 inhibitor such as disclosed in U.S. application Ser. No. 09/391,053, filed Sep. 7, 1999, and in U.S. provisional application No. 60/127,745, filed Apr. 5, 1999 (attorney file LA27*), employing dosages as set out herein. Preferred are the compounds designated as preferred in the above application.

[0224] The other antidiabetic agent may be a DP4 inhibitor such as disclosed in WO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278 (PROBIODRUG), WO99/61431 (PROBIODRUG), NVP-DPP728A (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine) (Novartis) (preferred) as disclosed by Hughes et al, Biochemistry, 38(36), 11597-11603, 1999, TSL-225 (tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (disclosed by Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540, 2-cyanopyrrolidides and 4-cyanopyrrolidides as disclosed by Ashworth et al, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and 2745-2748 (1996) employing dosages as set out in the above references.

[0225] The meglitinide which may optionally be employed in combination with the compound of formula I of the invention may be repaglinide, nateglinide (Novartis) or KAD1229 (PF/Kissei), with repaglinide being preferred.

[0226] The SGLT2 inhibitor of formula I will be employed in a weight ratio to the meglitinide, PPAR γ agonist, PPAR α/γ dual agonist, aP2 inhibitor or DP4 inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.2:1 to about 10:1.

[0227] The hypolipidemic agent or lipid-lowering agent which may be optionally employed in combination with the compounds of formula I of the invention may include 1,2,3 or more MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acid cotransporter inhibitors, upregulators of LDL receptor activity, bile acid sequestrants, and/or nicotinic acid and derivatives thereof.

[0228] MTP inhibitors employed herein include MTP inhibitors disclosed in U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat. No. 5,885,983 and U.S. application Ser. No. 09/175,180 filed Oct. 20, 1998, now U.S. Pat. No. 5,962,440. Preferred are each of the preferred MTP inhibitors disclosed in each of the above patents and applications.

[0229] All of the above U.S. Patents and applications are incorporated herein by reference.

[0230] Most preferred MTP inhibitors to be employed in accordance with the present invention include preferred MTP inhibitors as set out in U.S. Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No. 5,760,246.

[0231] The most preferred MTP inhibitor is 9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide

[0232] The hypolipidemic agent may be an HMG CoA reductase inhibitor which includes, but is not limited to, mevastatin and related compounds as disclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and related compounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Pat. No. 4,346,227, simvastatin and related compounds as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, disclosed in U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104, atavastatin (Nissan/Sankyo's nisvastatin (NK-104)) disclosed in U.S. Pat. No. 5,011,930, Shionogi-Astra/Zeneca visastatin (ZD-4522) disclosed in U.S. Pat. No. 5,260,440, and related statin compounds disclosed in U.S. Pat. No. 5,753,675., pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactone derivatives as disclosed in PCT application WO 86/03488, 6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivatives thereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a 3-substituted pentanedioic acid derivative) dichloroacetate, imidazole analogs of mevalonolactone as disclosed in PCT application WO 86/07054, 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed in French Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan and thiophene derivatives as disclosed in European Patent Application No. 0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat. No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No. 4,499,289, keto analogs of mevinolin (lovastatin) as disclosed in European Patent Application No. 0,142,146 A2, and quinoline and pyridine derivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322.

[0233] In addition, phosphinic acid compounds useful in inhibiting HMG CoA reductase suitable for use herein are disclosed in GB 2205837.

[0234] The squalene synthetase inhibitors suitable for use herein include, but are not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No. 5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid (phosphinyl-methyl)phosphonates as well as other known squalene synthetase inhibitors, for example, as disclosed in U.S. Pat. Nos. 4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K., Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2, 1-40 (1996).

[0235] In addition, other squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293, phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987, 109, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp 16, 17, 40-43, 48-51, Summary.

[0236] Other hypolipidemic agents suitable for use herein include, but are not limited to, fibric acid derivatives, such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol, and related compounds as disclosed in U.S. Pat. No. 3,674,836, probucol and gemfibrozil being preferred, bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, poly(diallylmethylamine) derivatives such as disclosed in U.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammonium chloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009, and other known serum cholesterol lowering agents.

[0237] The other hypolipidemic agent may be an ACAT inhibitor such as disclosed in, Drugs of the Future 24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor, Cl-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters”, Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85; “The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB100-containing lipoprotein”, Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; “RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor”, Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animals”, Krause et al, Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, Boca Raton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”, Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; “Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 6. The first water-soluble ACAT inhibitor with lipid-regulating activity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhanced hypocholesterolemic activity”, Stout et al, Chemtracts: Org. Chem. (1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd).

[0238] The hypolipidemic agent may be an upregulator of LD2 receptor activity such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

[0239] The hypolipidemic agent may be a cholesterol absorption inhibitor preferably Schering-Plough's SCH48461 as well as those disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).

[0240] The hypolipidemic agent may be an ileal Na⁺/bile acid cotransporter inhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).

[0241] Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin and ZD-4522.

[0242] The above-mentioned U.S. patents are incorporated herein by reference. The amounts and dosages employed will be as indicated in the Physician's Desk Reference and/or in the patents set out above.

[0243] The compounds of formula I of the invention will be employed in a weight ratio to the hypolipidemic agent (were present), within the range from about 500:1 to about 1:500, preferably from about 100:1 to about 1:100.

[0244] The dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.

[0245] The dosages and formulations for the hypolipidemic agent will be as disclosed in the various patents and applications discussed above.

[0246] The dosages and formulations for the other hypolipidemic agent to be employed, where applicable, will be as set out in the latest edition of the Physicians' Desk Reference.

[0247] For oral administration, a satisfactory result may be obtained employing the MTP inhibitor in an amount within the range of from about 0.01 mg/kg to about 500 mg and preferably from about 0.1 mg to about 100 mg, one to four times daily.

[0248] A preferred oral dosage form, such as tablets or capsules, will contain the MTP inhibitor in an amount of from about 1 to about 500 mg, preferably from about 2 to about 400 mg, and more preferably from about 5 to about 250 mg, one to four times daily.

[0249] For oral administration, a satisfactory result may be obtained employing an HMG CoA reductase inhibitor, for example, pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin in dosages employed as indicated in the Physician's Desk Reference, such as in an amount within the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.

[0250] The squalene synthetase inhibitor may be employed in dosages in an amount within the range of from about 10 mg to about 2000 mg and preferably from about 25 mg to about 200 mg.

[0251] A preferred oral dosage form, such as tablets or capsules, will contain the HMG CoA reductase inhibitor in an amount from about 0.1 to about 100 mg, preferably from about 5 to about 80 mg, and more preferably from about 10 to about 40 mg.

[0252] A preferred oral dosage form, such as tablets or capsules will contain the squalene synthetase inhibitor in an amount of from about 10 to about 500 mg, preferably from about 25 to about 200 mg.

[0253] The other hypolipidemic agent may also be a lipoxygenase inhibitor including a 15-lipoxygenase (15-LO) inhibitor such as benzimidazole derivatives as disclosed in WO 97/12615, 15-LO inhibitors as disclosed in WO 97/12613, isothiazolones as disclosed in WO 96/38144, and 15-LO inhibitors as disclosed by Sendobry et al “Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties”, Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al, “15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target for Vascular Disease”, Current Pharmaceutical Design, 1999, 5, 11-20.

[0254] The compounds of formula I and the hypolipidemic agent may be employed together in the same oral dosage form or in separate oral dosage forms taken at the same time.

[0255] The compositions described above may be administered in the dosage forms as described above in single or divided doses of one to four times daily. It may be advisable to start a patient on a low dose combination and work up gradually to a high dose combination.

[0256] The preferred hypolipidemic agent is pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin.

[0257] The other type of therapeutic agent which may be optionally employed with the SGLT2 inhibitor of formula I may be 1, 2, 3 or more of an anti-obesity agent including a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta drug and/or an anorectic agent.

[0258] The beta 3 adrenergic agonist which may be optionally employed in combination with a compound of formula I may be AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other known beta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 and CP331648 being preferred.

[0259] The lipase inhibitor which may be optionally employed in combination with a compound of formula I may be orlistat or ATL-962 (Alizyme), with orlistat being preferred.

[0260] The serotonin (and dopoamine) reuptake inhibitor which may be optionally employed in combination with a compound of formula I may be sibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), with sibutramine and topiramate being preferred.

[0261] The thyroid receptor beta compound which may be optionally employed in combination with a compound of formula I may be a thyroid receptor ligand as disclosed in WO97/21993 (U. Cal SF), WO99/00353 (KaroBio) and GB98/284425 (KaroBio), with compounds of the KaroBio applications being preferred.

[0262] The anorectic agent which may be optionally employed in combination with a compound of formula I may be dexamphetamine, phentermine, phenylpropanolamine or mazindol, with dexamphetamine being preferred.

[0263] The various anti-obesity agents described above may be employed in the same dosage form with the compound of formula I or in different dosage forms, in dosages and regimens as generally known in the art or in the PDR.

[0264] In carrying out the method of the invention for treating diabetes and related diseases, a pharmaceutical composition will be employed containing the compounds of structure I, with or without other antidiabetic agent(s) and/or antihyperlipidemic agent(s) and/or other type therapeutic agents in association with a pharmaceutical vehicle or diluent. The pharmaceutical composition can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration, such as pharmaceutically acceptable carriers, excipients, binders and the like. The compounds can be administered to mammalian species including humans, monkeys, dogs, etc. by an oral route, for example, in the form of tablets, capsules, beads, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations, or they can be administered intranasally or in transdermal patches. Typical solid formulations will contain from about 10 to about 500 mg of a compound of formula I. The dose for adults is preferably between 10 and 2,000 mg per day, which can be administered in a single dose or in the form of individual doses from 1-4 times per day.

[0265] A typical injectable preparation is produced by aseptically placing 250 mg of compounds of structure I into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.

[0266] SGLT2 inhibitor activity of the compounds of the invention may be determined by use of an assay system as set out below.

[0267] Assay for SGLT2 Activity

[0268] The mRNA sequence for human SGLT2 (GenBank #M95549) was cloned by reverse-transcription and amplification from human kidney mRNA, using standard molecular biology techniques. The cDNA sequence was stably transfected into CHO cells, and clones were assayed for SGLT2 activity essentially as described in Ryan et al. (1994). Evaluation of inhibition of SGLT2 activity in a clonally selected cell line was performed essentially as described in Ryan et al., with the following modifications. Cells were grown in 96-well plates for 2-4 days to 75,000 or 30,000 cells per well in F-12 nutrient mixture (Ham's F-12), 10% fetal bovine serum, 300 ug/ml Geneticin and penicillin-streptomycin. At confluence, cells were washed twice with 10 mM Hepes/Tris, pH 7.4, 137 mM N-methyl-D-glucamine, 5.4 mM KCl, 2.8 mM CaCl₂, 1.2 mM MgSO₄. Cells then were incubated with 10 μM [¹⁴C]AMG, and 10 μM inhibitor (final DMSO=0.5%) in 10 μM Hepes/Tris, pH 7.4, 137 mM NaCl, 5.4 mM KCl, 2.8 mM CaCl₂, 1.2 MM MgSO₄ at 37° C. for 1.5 hr. Uptake assays were quenched with ice cold 1× PBS containing 0.5 mM phlorizin, and cells were then lysed with 0.1% NaOH. After addition of MicroScint scintillation fluid, the cells were allowed to shake for 1 hour, and then [¹⁴C]AMG was quantitated on a TopCount scintillation counter. Controls were performed with and without NaCl. For determination of EC₅₀ values, 10 inhibitor concentrations were used over 2 log intervals in the appropriate response range, and triplicate plates were averaged across plates.

[0269] Ryan M J, Johnson G, Kirk J, Fuerstenberg S M, Zager R A and Torok-Storb B. 1994. HK-2: an immortalized proximal tubule epithelial cell line from normal adult human kidney. Kidney International 45: 48-57.

[0270] The following Working Examples represent preferred embodiments of the present invention. All temperatures are expressed in degrees Centigrade unless otherwise indicated.

EXAMPLE 1

[0271]

[0272] A. 4-Methyl-2′-hydroxybenzhydrol

[0273] To a 500 ml round bottom flask containing 100 mL of THF under Ar was added commercial 1 M p-methylphenyl magnesium bromide/Et₂O (100 mL, 100 mmol). Subsequently, salicylaldehyde (4.9 g, 40.3 mmol) was added dropwise in four equal portions spaced over 2 hr. After 20 min, once HPLC analysis revealed the aldehyde to be consumed, the reaction was quenched by dropwise addition of 26 ml of sat'd NH₄Cl/H₂O to produce a white paste. To this suspension was added 200 mL of PhMe and sufficient H₂O to permit stirring. The organic layer was decanted whereupon the white paste was triterated a second time with 1:1 THF/PhMe. After decanting, the combined organic layers were concentrated using a rotary evaporator to obtain 9.7 g of crude 4-methyl-2′-hydroxybenzhydrol.

[0274] B. 2-(4′-Methylbenzyl)phenol

[0275] To a solution of crude Part A 4-methyl-2′-hydroxybenzhydrol (9.7 g containing no more than 40 mmol) in 175 mL of MeOH was added 0.59 g of 10% Pd/C and 1.75 mL of TFA. The suspension was stirred for 40 hr under 1 atmos. H₂, filtered through celite and concentrated to yield 8.6 of crude 2-(4′-methylbenzyl)phenol as an oil.

[0276] C.

[0277] A mixture of Part B 2-(p-methylbenzyl)phenol (8.6 g, containing no more than 37 mmol), 2,6-di-t-butyl-4-methylpyridine (10.6 g, 52 mmol), 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (17.5 g, 43 mmol) in 270 mL CH₂Cl₂ was stirred until homogeneous prior to cooling to 0°. After addition of AgOTf (12.2 g, 47 mmol) to the cold solution, the reaction was stirred 1 hr prior to addition of additional 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (7.6 g, 18 mmol) and AgOTf (6.5 g, 25 mmol). An additional 100 mL of CH₂Cl₂ was required to dilute the suspension to maintain stirring. After 30 min, the suspension was directly loaded on a silica gel column which was eluted initially with 25% EtOAc/hexane. The undesired minor a anomeric product eluted first followed by desired title β-O-glucoside tetraacetate as the eluant increased from 25-35% EtOAc/hexane. After concentration, the crude product, dissolved in the minimum EtOAc, was induced to crystallize by addition of hexane. A total of 8.25 g of pure desired title beta isomer plus ^(˜)3 g of impure material was obtained.

[0278] D.

[0279] To a solution of Part C compound (8.25 g, 15 mmol) in 35 mL of CH₂Cl₂ was added MeOH (200 mL) followed by 0.7 mL of 1 N NaOH in H₂O. After 2 hr, when the reaction was complete as determined by HPLC, the volatiles were removed using a rotary evaporator. The residue, dissolved in a 1:10:10 mixture of H₂O/CH₂Cl₂/MeOH (42 mL), was diluted with CH₂Cl₂ (400 mL) and subsequently loaded onto a silica gel column. The desired product (5.68 g), after elution with 5-7% of MeOH/CH₂Cl₂ and removal of the volatiles, was isolated as a white solid.

[0280]¹H NMR (400 MHz, CD₃OD) δ 7.15-7.08 (m, 4H), 7.05 (m, 3H) 6.91 (m,1H),4.93 (d, 1H,obscured), 4.04 (d, 1H, J=14 Hz), 3.95 (d, 1H, J=14 Hz), 3.88 (d, 1H, J=12 Hz), 3.68 (dd, 1H, J=12, 3 Hz), 3.52-3.36 (m, 4H), 2.27 (s, 3H).

[0281] HPLC retention time: 6.88 min, Zorbax C-18 4.6×75 mm, 2.5 mL/min, detection at 220 nm, 8 min gradient 0-100% B hold 3 min at 100% B. Solvent A: 10% MeOH/H₂O+0.2% H₃PO₄. Solvent B: 90% MeOH/H₂O+0.2% H₃PO₄.

[0282] Anal Calcd for C₂₀H₂₄O₆ LC-MS (M+Na) 383

EXAMPLE 2

[0283]

[0284] A. 2-(4′-Ethylbenzyl)phenol

[0285] A 60% dispersion of NaH/mineral oil (144 mg, 3.6 mmol) under Ar was added dropwise to a stirred solution of phenol (284 mg, 3 mmol) in PhMe (15 mL). After 10 min, p-ethylbenzyl chloride (1.23 g, 5.3 mmol) in PhMe (2 mL) was added prior to heating the reaction for 6 hr at 800. After cooling, the volatiles were removed using a rotary evaporator and the residue dissolved in 15 mL of MeOH. The MeOH solution was extracted 4× with hexane prior to concentration. The resulting residue was dissolved in 1:1 EtOAc/H₂O (100 mL), the pH adjusted to 5 and the two phases separated. After drying over Na₂SO₄ and removal of the EtOAc, 390 mg of crude title 2-(4′-ethylbenzyl)phenol was obtained. Prep HPLC yielded 275 mg of clean 2-(4′-ethylbenzyl)phenol.

[0286] B.

[0287] A suspension of 2-(4′-ethylbenzyl)phenol (212 mg, 1 mmol), 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (822 mg, 2 mmol), and Ag₂O (232 mg, 2 mmol) in 4 mL lutidine was stirred for 14 hr at 200. Since the conversion was 80% complete by HPLC, an additional 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (411 mg, 1 mmol) and Ag₂O (116 mg, 1 mmol) was added and the reaction continued for 24 hr. Afterwards, H₂O (5 mL) and 1N aq. NaOH (2 mL) was added and the suspension stirred for 16 hr. The reaction mixture was extracted twice with EtOAc. The EtOAc extracts were dried over Na₂SO₄ before concentration. The resulting residue was purified by Prep HPLC to yield 8.7 mg of final product.

[0288]¹H NMR (400 MHz, CD₃OD) δ 7.15 (m, 4H), 7.08-7.01 (m, 3H), 6.91 (m,1H), 4.91 (d, 1H, obscured), 4.08 (d, 1H, J=14 Hz), 3.95 (d, 1H, J=14 Hz), 3.88 (d, 1H, J=12 Hz), 3.68 (dd, 1H, J=12, 3 Hz), 3.53-3.37 (m, 4H), 2.57 (q, 2H, J=7 Hz), 1.18 (t, 3H, J=7 Hz).

[0289] HPLC retention time: 7.32 min, Zorbax C-18 4.6×75 mm, 2.5 mL/min, detection at 220 nm, 8 min gradient 0-100% B hold 3 min at 100% B. Solvent A: 10% MeOH/H₂O+0.2% H₃PO₄. Solvent B: 90% MeOH/H₂O+0.2% H₃PO₄.

[0290] Anal Calcd for C₂₁H₂₆O₆ LC-MS (M+Na) 397

EXAMPLE 3

[0291]

[0292] A. 2-Benzyloxy-4′-methyldiphenyl Ether

[0293] A mixture of 2-benzyloxyphenol (5 g, 2.49 mmol), Cu(OAc)₂ (452 mg, 2.49 mmol), p-methylphenylboronic acid (339 mg, 2.49 mmol), and activated 4A° molecular sieves (10 g) in CH₂Cl₂ (8 mL) was stirred for a few minutes prior to the addition of Et₃N (1.26 g, 12.5 mmol) followed by pyridine (0.99 g, 12.5 mmol. After stirring for 20 hr, the reaction was filtered through celite which was washed with CH₂Cl₂. The filtrate was concentrated and the residue chromatographed on silica gel using 4% EtOAc/hexane to elute 280 mg (39%) of the desired title 2-benzyloxy-4′-methyldiphenyl ether.

[0294] B. 2-Hydroxy-4′-methyldiphenyl Ether

[0295] A solution of Part A compound (280 mg, 0.96 mmol) in MeOH (50 mL) over Pd/C (30 mg) was stirred overnight under 1 atmosphere of H₂. The reaction was filtered through celite which was subsequently washed with MeOH and CH₂Cl₂. Removal of the solvent yielded 190 mg of title 2-hydroxy-4′-methyldiphenyl ether.

[0296] C.

[0297] A suspension comprised of Part B compound (94 mg, 0.47 mmol), 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (185 mg, 0.45 mmol),and Ag₂O (62 mg, 0.27 mmol) in 1.0 mL lutidine was stirred for 19 hr at 650. Since the reaction was 50% complete by HPLC analysis, additional 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (185 mg, 0.45 mmol) and Ag₂O (62 mg, 0.27 mmol) were added and the reaction continued for 3 more hours. After cooling, 1 N HCl (25 mL) was added prior to 3 EtOAc extractions (total volume 75 mL). The combined organic extracts were washed with H₂O, aq. NaHCO₃, and brine prior to drying over MgSO₄. After removal of the solvent under vacuum, 50 mg of crude product was obtained. Without purification, this material was stirred overnight in 1:2:3 H₂O/THF/MeOH (1 mL) containing LiOH (4.7 mg, 0.17 mmol). The volatiles were removed and the residue was purified by Prep HPLC. A 10 min. gradient elution (30% to 90% MeOH/H₂O) from a YMC S5 C18 reverse phase column eluted 26 mg of final O-glucoside after lyophilization.

[0298]¹H NMR (400 MHz, CD₃OD) δ 2.29 (s, 3H), 3.34-3.42 (m, 4H), 3.67 (dd, 1H, J=4.8, 11.3 Hz), 3.85 (dd, 1H, J=2.2, 11.9 Hz), 4.95 (d, 1H, J=7.0 Hz), 6.82-7.29 (m, 8H).

[0299] HPLC retention time: 6.47 min, 93% purity, Zorbax C-18 4.6×75 mm, 2.5 mL/min, detection at 220 nm, 8 min gradient 0-100% B hold 3 min at 100% B. Solvent A: 10% MeOH/H₂O+0.2% H₃PO₄. Solvent B: 90% MeOH/H₂O+0.2% H₃PO₄.

[0300] Anal Calcd for C₁₉H₂₂O₇ Low Res. MS [M+Na]=385, [M+NH4]=380, [2M+NH4]=742, [M−H]=361, [2M−H]=723.

EXAMPLE 4

[0301] A.

[0302] A suspension of 2-nitrophenol (1.67 g, 12 mmol), 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (4.5 g, 10.9 mmol), and Ag₂O (1.6 g, 7.1 mmol) in 20 mL lutidine was stirred for 19 hr at 200. The reaction was diluted with 250 mL of CH₂Cl₂ and filtered through celite. After washing the celite with additional CH₂Cl₂, the combined rganic fraction was concentrated to yield a yellow residue. Triteration (4×) with MeOH dissolved most impurities to yield 4.15 of the desired title 2-nitrophenyl-o-glucoside.

[0303] B.

[0304] Crude Part A compound (2 g), partially dissolved in 35 mL of 2:2:3 THF/DCE/MeOH containing 0.2 g of 10% Pd/C, was stirred for 5 hr under 1 atmosphere H₂ for 16 hr prior to filtration through celite. The filtrate, including the MeOH washes of the celite pad, were concentrated to yield 1.8 of title o-anilino-O-glucoside.

[0305] C.

[0306] A mixture of Part B compound (100 mg, 0.23 mmol), Pd(OAc)₂ (2.5 mg, 0.01 mmol), BINAP (0.8 mg, 0.0014 mmol) and phenyl triflate (51 mg, 0.23 mmol) were stirred for 5 min in PhMe (1 mL) containing 1 drop of Et₃N before adding Cs₂CO₃ (103 mg, 0.32 mmol). Upon heating to 1020, the bright yellow solution became red. After 15 hr HPLC showed a new peak plus residual. An attempt to drive the conversion by addition of the other reaction components was not successful. The reaction, after cooling to 20°, was diluted with EtOAc and filtered through celite. The filtrate was concentrated and the residue chromatographed on silica gel using 3:7 EtOAc/hexane to elute 10 mg of desired title product.

[0307] D.

[0308] Part C tetra acetate (10 mg, 0.019 mmol) was stirred overnight in 1:2:3 H₂O/THF/MeOH (0.6 mL) containing LiOH (1 mg, 0.023 mmol). The volatiles were removed after neutralization with 1 N HCl. The residue was purified by Prep HPLC on a YMC S5 C18 reverse phase column employing a 10 min. gradient elution (30% to 90% MeOH/H₂O) to obtain 3 mg of final glucoside after lyophilization.

[0309]¹H NMR (500 MHz, CD₃OD) δ 3.37-3.52 (m, 4H), 3.72 (dd, 1H, J=5 Hz), 3.89 (dd, 1H, J=2 Hz), 4.74 (d,1H, J=8 Hz), 6.77-7.28 (m, 9H) HPLC retention time: 6.2 min, 100% purity, Zorbax C-18 4.6×75 mm, 2.5 mL/min, detection at 220 nm, 8 min gradient 0-100% B hold 3 min at 100% B. Solvent A: 10% MeOH/H₂O+0.2% H₃PO₄. Solvent B: 90% MeOH/H₂O+0.2% H₃PO₄.

[0310] Anal Calcd for C₁₈H₂₁NO₆ Low Res. MS [M+H]=348

EXAMPLE 5

[0311]

[0312] A. 2-Hydroxy-4′-diphenyl Sulfide

[0313] 60% NaH/mineral oil (260 mg, 6.5 mmol) was washed with pentane twice prior to being suspended with stirring under Ar in THF (10 mL) at 0° whereupon neat o-bromophenol (500 μL, 746 mg, 4.3 mmol) was added. After stirring for 1 hr at 200, the solution was cooled to −780 and 1.28 M t-BuLi/hexane (3.7 mL, 4.7 mmol) was added. After 10 min, 3 mL of a THF solution of p-tolyl disulfide (1.06 g, 4.3 mmol) was added. The reaction was stirred for 10 min before warming to 0° at which temperature it was maintained for 1 hr. The reaction was quenched by addition of 2 mL of satd aq. NH₄Cl prior to dilution with 150 mL of EtOAc. The EtOAc phase was washed with satd aq. NH₄Cl, dried over MgSO₄ and concentrated to yield a yellow oil (910 mg). Chromatography on silica gel using 5:1 hexane/EtOAc yielded 2-hydroxy-4′-diphenyl sulfide (555 mg) as a clear oil.

[0314] B.

[0315] A solution of Part A compound (300 mg, 1.39 mmol), 2,6-di-t-butyl-4-methylpyridine (387 mg, 1.88 mmol), 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (661 mg, 1.61 mmol) in 9 mL CH₂Cl₂ was stirred until homogeneous prior to cooling to 0°). After addition of AgOTf (456 mg, 1.88 mmol) to the cold solution, the reaction was stirred 2.5 hr prior to addition of additional 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (274 mg, 0.66 mmol) and AgOTf (157 mg, 0.61 mmol). After 2 hr, the suspension was directly loaded on a silica gel column which was eluted initially with 1:2 EtOAc/hexane. The minor undesired α-anomer (99 mg) eluted first followed by the desired title tetra-acetoxy-β-O-glucoside (660 mg).

[0316] C.

[0317] Part B tetra-acetate (525 mg, 0.96 mmol) was stirred 6 hr in 1:2:3 H₂O/THF/MeOH (9.6 mL) containing LiOH (40 mg, 1 mmol). The volatiles were removed after neutralization with 1 N HCl. 20% of residue was purified by Prep HPLC on a YMC S5 C18 reverse phase column employing a 10 min. gradient elution (50% to 90% MeOH/H₂O) to obtain 24 mg of final glucoside after lyophilization.

[0318]¹H NMR (400 MHz, CD₃OD) δ 7.29 (m, 2H), 7.18 (m, 4H), 6.88 (m, 2H), 4.98 (d, 1H, J=7.0 Hz), 3.88 (m, 1H), 3.70 (dd, 1H, J=4.8, 11.9), 3.43 (m, 4H), 2.34 (s, 3H).

[0319] HPLC: 6.85 min. retention time; HI=100%; YMC S3 column ODS 4.6×50 mm; 2.5 mL/min, detection at 220 nm, 0-100%B over 8 min, hold for 5 min. Solvent A: 10% MeOH/H₂O+0.2% H₃PO₄. Solvent B: 90% MeOH/H2O+0.2% H3PO4.

[0320] Anal Calcd for C₁₉H₂₂O₆S LC-MS: [M+H]379, [M+Na]401, [2M+Na]779.

EXAMPLES 6 TO 99

[0321] In a manner analogous to that of Examples 1 to 5, the compounds of the invention in the following table were prepared.

MS or LC/MS Ex. # A R¹ R² R³ R⁴ R⁵* (M + H)⁺ 6 CH₂ H H H H H 347 7 CH₂ H H H H 2-HO 363 8 CH₂ H H H H 4-MeO 377 9 CH₂ H H H H 4-tBu 403 10 CH₂ H H H H 4-MeS 393 11 CH₂ H H H H 4-Ph 423 12 CH₂ H H H H 4-BnO 453 13 CH₂ H H H H 4-iPr 389 14 CH₂ H H H H 4-Cl 381 15 CH₂ H H H H 4-MeSO₂ 425 16 CH₂ H H H H 4-CF₃ 415 17 CH₂ H H H H 4-CF₃O 431 18 CH₂ H H H H 4-OCH₂CO₂H 426 19 CH₂ H H H H 4-OCH₂CO₂Me 435 20 CH₂ H H H H 4-OCH₂CONEt₂ 476 21 CH₂ H H H H 4-OCH₂CH₂NMe₂ 434 22 CH₂ H H H H 4-styrenyl 449 23 CH₂ H H H H 3-Me 361 24 CH₂ H H H H 3-MeO 377 25 CH₂ H H H H 2-MeO 377 26 CH₂ H H H H 2-Et 375 27 CH₂ H H H H 2,4-Me₂ 375 28 CH₂ H H H H 3-Cl, 4-Me 394 29 CH₂ H H H H 3,4-OCH₂O 391 30 CH₂ Cl H H H H 381 31 CH₂ Me H H H H 361 32 CH₂ H Me H H H 361 33 CH₂ H F H H H 365 34 CH₂ H Cl H H H 381 35 CH₂ H (p-MeBn) H H H 465 36 CH₂ H Cl H H 2-HO, 5-Cl 431 37 CH₂ H Cl H Br H 459 38 CH₂ H Br H Br H 503 39 CH₂ H (1,1,3,3-Me₄—Bu) H H 2,4-Cl₂ 527 40 CH₂ H H MeO H H 377 41 CH₂ H H MeO H 4-Me 391 42 CH₂ H H PrO H H 405 43 CH₂ H H Me H H 361 44 CH₂ H H Cl H H 381 45 CH₂ H H H Cl H 381 46 CH₂ H H H Me 4-MeS 407 47 CH₂ H H H Me 4-HO 377 48 CH₂ H H H Me 4-Me 375 49 CH₂ H H H Me 4-MeSO₂ 439 50 Bond H H H H H 333 51 (CH₂)₂ H H H H H 361 52 (CH₂)₃ H H H H H 375 53 OCH₂ H H H H H 363 54 OCH₂CH₂ H H H H 4-MeO 407 55 NH H H H H 4-Me 361 56 NHCH₂ H H H H H 362 57 NHCH₂ H H H H 4-Me 376 58 NHCH₂ H H H H 2,3-Benzo 412 59 NHCH₂ H H H H 4-MeO 392 60 NHCH₂ H H H H 4-CF₃ 430 61 NHCH₂ H H H H 3-Me 376 62 NHCH₂ H H H H 4-Me₂N 405 63 NHCH₂ H H H H 4-MeS 408 64 NHCH₂ H H H H 2-Me 376 65 NHCH₂ H H H H 2,3-OCH₂O 406 66 NHCH₂CH₂ H H H H H 376

70 CH₂ Me H H H 4-Me 392 (M + NH4) 71 CH₂ Me H H H 4-Et 387 (M − H) 72 CH₂ Me H H H 4-Cl 73 CH₂ Me H H H 4-MeS 74 CH₂ Me H H H 4-MeO 75 CH₂ Me H H H 4-HO 76 CH₂ Me H H H 4-MeSO₂ 77 CH₂ Me H H H 4-CF₃O 502 (M − H + MeCO2⁻) 78 CH₂ Me H H H 4-CF₃ 79 CH₂ Me H H H 4-Ac 80 CH₂ Me H H H 4-HOCH₂ 81 CH₂ Me H H H 4-CHF₂O 82 CH₂ H H H Me 4-Et 83 CH₂ H H H Me 4-CHF₂O 84 CH₂ H H H Me H 378 (M + NH4) 85 CH₂ H H H Me 4-Cl 86 CH₂ H H H Me 4-AC 87 CH₂ H H H Me 4-HOCH₂ 88 CH₂ H H H Me 4-CF₃O 89 CH₂ H H H Me 4-CH₃O 408 (M + NH4) 90 CH₂ H H H H 4-Ac 91 CH₂ H H H H 4-HOCH₂ 92 CH₂ H H H H 4-CHF₂O 93 CH₂ H H H H 2-Pyridine 94 CH₂ H H H H 3-Pyridine 95 CH₂ H H H H 2-Oxazole 96 CH₂ H H H H 2-Thiazole 97 CH₂ H H H H 2-Benzthiazole 98 CH₂ H H H H 3-Quinoline 99 CH₂ Me H H H 2-Oxazole 100 CH₂ H H H Me 2-Thiazol 101 CH₂ H H H Me 2-Oxazole 

What is claimed:
 1. A compound having the structure

wherein when Y is

or heteroaryl; R¹, R², R³, and R⁴ are the same or different and are independently selected from hydrogen, OH, OR⁷, lower alkyl, or halogen, or two of R¹, R² R³, and R⁴ together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂; R⁵ and R⁶ are the same or different and are independently selected from hydrogen, OH, OR^(7a), —OAryl, —OCH₂Aryl, lower alkyl, cycloalkyl, Aryl, arylalkyl, CF₃, arylalkenyl, —OCHF₂, —OCF₃, halogen, —CN, —CO₂R^(7b), —CO₂H, COR^(8f), CHOHR^(8g), CH(OR⁷)R^(8h), —CONR⁸R^(8a), —NHCOR^(7c), —NHSO₂R^(7d), —NHSO₂Aryl, SR^(7e), —SOR^(7f), SO₂R^(7g), —SO₂Aryl, —OCH₂CO₂R^(7i), —OCH₂CO₂H, —OCH₂CONR^(8b)R^(8c), —OCH₂CH₂NR^(8d)R^(8e), or a five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂, or R⁵ and R⁶ together with the carbons to which they are attached form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂; R⁷, R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), R^(7f), R^(7h) and R^(7i) are independently lower alkyl; R⁸, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h) are the same or different and are independently selected from hydrogen, alkyl,aryl, arylalkyl, cycloalkyl, or together with the nitrogen to which they are attached form an annelated five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂; A is O(CH₂)_(m), S, NH(CH₂)_(m), or (CH₂)_(n) where n is 0-3 and m is 0-2, and a pharmaceutically acceptable salt thereof, all stereoisomers thereof, and all prodrug esters thereof, with the following provisos that where A is CH₂ and

and 1) when R¹ is OH and R³ is alkyl, at least one of R¹, R⁴, R⁵ and R⁶ is not hydrogen; 2) when R² and R³ are OH, at least one of R¹, R⁴, R⁵ and R⁶ is not hydrogen; 3) when R² is methyl, R⁵is OH, and R⁶ is alkyl, at least one of R¹, R³, and R⁴ is not hydrogen; and 4) when R² is chlorine, at least one of R¹, R³, R⁴, R⁵ and R⁶ is not hydrogen.
 2. The compound as defined in claim 1 wherein Y is


3. The compound as defined in claim 1 wherein Y is heteroaryl.
 4. The compound as defined in claim 1 wherein A is O(CH₂)_(m).
 5. The compound as defined in claim 1 wherein A is S.
 6. The compound as defined in claim 1 wherein A is NH(CH₂)_(m).
 7. The compound as defined in claim 1 wherein A is (CH₂)_(n).
 8. The compound as defined in claim 1 having the structure

wherein A is CH₂ or O or S.
 9. The compound as defined in claim 8 wherein A is CH₂; R¹ is H, halogen, or alkyl, and R², R³ and R⁵ are each hydrogen.
 10. The compound as defined in claim 1 having the structure


11. The compound as defined in claim 1 having the structure

A R¹ R² R³ R⁴ R⁵ CH₂ H H H H H CH₂ H H H H 2-HO CH₂ H H H H 4-MeO CH₂ H H H H 4-tBu CH₂ H H H H 4-MeS CH₂ H H H H 4-Ph CH₂ H H H H 4-BnO CH₂ H H H H 4-iPr CH₂ H H H H 4-Cl CH₂ H H H H 4-MeSO₂ CH₂ H H H H 4-CF₃ CH₂ H H H H 4-CF₃O CH₂ H H H H 4-OCH₂CO₂H CH₂ H H H H 4-OCH₂CO₂Me CH₂ H H H H 4-OCH₂CONEt₂ CH₂ H H H H 4-OCH₂CH₂NMe₂ CH₂ H H H H 4-styrenyl CH₂ H H H H 3-Me CH₂ H H H H 3-MeO CH₂ H H H H 2-MeO CH₂ H H H H 2-Et CH₂ H H H H 2,4-Me₂ CH₂ H H H H 3-Cl,4-Me CH₂ H H H H 3,4-OCH₂O CH₂ Cl H H H H CH₂ Me H H H H CH₂ H Me H H H CH₂ H F H H H CH₂ H Cl H H H CH₂ H (p-MeBn) H H H CH₂ H Cl H H 2-HO,5-Cl CH₂ H Cl H Br H CH₂ H Br H Br H CH₂ H (1,1,3,3- H H 2,4-Cl₂ Me₄-Bu) CH₂ H H MeO H H CH₂ H H MeO H 4-Me CH₂ H H PrO H H CH₂ H H Me H H CH₂ H H Cl H H CH₂ H H H Cl H CH₂ H H H Me 4-MeS CH₂ H H H Me 4-HO CH₂ H H H Me 4-Me CH₂ H H H Me 4-MeSO₂ Bond H H H H H (CH₂)₂ H H H H H (CH₂)₃ H H H H H OCH₂ H H H H H OCH₂CH₂ H H H H 4-MeO NH H H H H 4-Me NHCH₂ H H H H H NHCH₂ H H H H 4-Me NHCH₂ H H H H 2,3-Benzo NHCH₂ H H H H 4-MeO NHCH₂ H H H H 4-CF₃ NHCH₂ H H H H 3-Me NHCH₂ H H H H 4-Me₂N NHCH₂ H H H H 4-MeS NHCH₂ H H H H 2-Me NHCH₂ H H H H 2,3-OCH₂O NHCH₂CH₂ H H H H H

A R¹ R² R³ R⁴ R⁵ CH₂ Me H H H 4-Me CH₂ Me H H H 4-Et CH₂ Me H H H 4-Cl CH₂ Me H H H 4-MeS CH₂ Me H H H 4-MeO CH₂ Me H H H 4-HO CH₂ Me H H H 4-MeSO₂ CH₂ Me H H H 4-CF₃O CH₂ Me H H H 4-CF₃ CH₂ Me H H H 4-Ac CH₂ Me H H H 4-HOCH₂ CH₂ Me H H H 4-CHF₂O CH₂ H H H Me 4-Et CH₂ H H H Me 4-CHF₂O CH₂ H H H Me H CH₂ H H H Me 4-Cl CH₂ H H H Me 4-AC CH₂ H H H Me 4-HOCH₂ CH₂ H H H Me 4-CF₃O CH₂ H H H H 4-Ac CH₂ H H H H 4-HOCH₂ CH₂ H H H H 4-CHF₃O

A R¹ R² R³ R⁴ CH₂ H H H H 2-Pyridine CH₂ H H H H 3-Pyridine CH₂ H H H H 2-Oxazole CH₂ H H H H 2-Thiazole CH₂ H H H H 2-Benzthiazole CH₂ H H H H 3-Quinoline CH₂ H Me H H 2-Oxazole CH₂ H H H Me 2-Thiazol CH₂ H H H Me 2-Oxazole.

*R⁶ = H unless otherwise indicated A R¹ R² R³ R⁴ R⁵ CH₂ H H H H 4-MeO CH₂ H H H H 4-tBu CH₂ H H H H 4-MeS CH₂ H H H H 4-iPr CH₂ H H H H 4-Cl CH₂ H H H H 4-CF₃ CH₂ H H H H 4-CF₃O CH₂ Me H H H H CH₂ H H H Me 4-MeS CH₂ H H H Me 4-Me CH₂ Cl H H H H


12. The compound as defined in claim 1 having the structure.
 13. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor.
 14. A pharmaceutical combination comprising an SGLT2 inhibitor compound as defined in claim 1 and an antidiabetic agent other than an SGLT2 inhibitor, an anti-obesity agent, and/or a lipid-lowering agent.
 15. The pharmaceutical combination as defined in claim 14 comprising said SGLT2 inhibitor compound and an antidiabetic agent.
 16. The combination as defined in claim 15 wherein the antidiabetic agent is 1, 2, 3 or more of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, a PPAR α/γ dual agonist, an aP2 inhibitor, a DP4 inhibitor, an insulin sensitizer, a glucagon-like peptide-l (GLP-l), insulin and/or a meglitinide.
 17. The combination as defined in claim 16 wherein the antidiabetic agent is 1, 2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, Gl-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, AR-HO39242, GW-409544, KRP297, AC2993, LY315902, and/or NVP-DPP-728A.
 18. The combination as defined in claim 15 wherein the compound is present in a weight ratio to the antidiabetic agent within the range from about 0.01 to about 300:1.
 19. The combination as defined in claim 14 wherein the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound, and/or an anorectic agent.
 20. The combination as defined in claim 19 wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, and/or mazindol.
 21. The combination as defined in claim 14 wherein the lipid lowering agent is an MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, or an ACAT inhibitor.
 22. The combination as defined in claim 21 wherein the lipid lowering agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, and/or LY295427.
 23. The combination as defined in claim 21 wherein the aP2 inhibitor is present in a weight ratio to the lipid-lowering agent within the range from about 0.01 to about 100:1.
 24. A method for treating diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, diabetic complications, or elevated blood levels of free fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis, hypertension, or for increasing high density lipoprotein levels, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound as defined in claim
 1. 25. The method as defined in claim 24 where the compound administered has the structure

A R¹ R² R³ R⁴ R⁵ CH₂ H H H H 4-MeO CH₂ H H H H 4-tBu CH₂ H H H H 4-MeS CH₂ H H H H 4-iPr CH₂ H H H H 4-Cl CH₂ H H H H 4-CF₃ CH₂ H H H H 4-CF₃O CH₂ Me H H H H CH₂ H H H Me 4-MeS CH₂ H H H Me 4-Me.


26. A method for treating type II diabetes which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound as defined in claim 1 alone or in combination with one, two or more other antidiabetic agent(s), and/or one, two or more hypolipidemic agent(s). 